Acetone solvate of dimethoxy docetaxel and its process of preparation

Abstract

This invention discloses and claims an acetone solvate of dimethoxydocetaxel or 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and its preparation by crystallization from an aqueous/acetone solution.

1. An acetone solvate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 
     
     
       2. An acetone solvate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate comprising from about 5 to about 7 percent by weight of acetone. 
     
     
       3. A process for the preparation of the acetone solvate of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, which comprises:
 crystallizing 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate from a mixture of water and acetone, which comprises seeding the solution with a suspension of said product in an acetone/water mixture and then subsequently treating with water, and which comprises drying the product obtained under reduced pressure. 
 
     
     
       4. The process as set forth in  claim 3 , wherein the seeding is carried out at a concentration of from about 60 to about 80 g per liter of a mixture comprising an acetone/water ratio by volume of from about 65/35 to about 75/25. 
     
     
       5. The process as set forth in  claim 4 , wherein the seeding is carried out in a mixture comprising an acetone/water ratio by volume of about 68/32. 
     
     
       6. The process as set forth in  claim 3 , wherein the acetone/water mixture by volume at the end of precipitation is from about 70/30 to about 30/70. 
     
     
       7. The process as set forth in  claim 6 , wherein the acetone/water mixture by volume at the end of precipitation is about 45/55. 
     
     
       8. The process as set forth in  claim 3 , wherein the crystallization process takes place at about 20±5° C. 
     
     
       9. The process as set forth in  claim 4 , wherein the crystallization process takes place at about 20±5° C. 
     
     
       10. The process as set forth in  claim 5 , wherein the crystallization process takes place at about 20±5° C. 
     
     
       11. The process as set forth in  claim 6 , wherein the crystallization process takes place at about 20±5° C. 
     
     
       12. The process as set forth in  claim 7 , wherein the crystallization process takes place at about 20±5° C. 
     
     
       13. The process as set forth in  claim 3 , wherein drying is carried out at a temperature in the range of from about 30 and about 60° C. 
     
     
       14. The process as set forth in  claim 13 , wherein drying is further carried out under a pressure in the region of 0.7 kPa. 
     
     
       15. The process as set forth in  claim 3 , wherein drying is carried out at a temperature of about 40° C. under a pressure in the region of 0.7 kPa. 
     
     
       16. The process as set forth in  claim 3 , wherein the preparation is carried out directly starting from the acetone solution of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained by deprotection in an acid medium of the ester 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate.